See also Mannucci PM. Abnormal hemostasis tests and bleeding in chronic liver disease: are they related? No. This issue, pp 721–3.

commonly used prognostic indexes of chronic liver disease as

The concept that liver failure determines an acquired coagulo- the Child-Pugh or Mayo End-Stage Liver Disease (MELD)pathy causing bleeding has been ﬁrmly established for many scores [5,6]. Because of the defective synthesis of FXII, FXI,years [1]. However, the role played by coagulation defects in high-molecular-weight kininogen and prekallikrein, the APTTdetermining bleeding in cirrhotics has recently been questioned is also prolonged in advanced liver cirrhosis [1]. These screening[2]. It has been argued that patients with cirrhosis bleed more tests are cheap and easy to perform and have been consideredinfrequently than patients with an apparently similar degree of clinically useful, but have several limitations. Firstly, they docongenital coagulation deﬁciencies [2]. In addition, when not reproduce Ôin vivoÕ coagulation, because platelets and othercirrhotics bleed, the sites and types of bleeding are different, blood cells are removed from platelet poor plasma and severalmainly involving the gastrointestinal tract. Moreover, global substances, non-physiological or in non-physiological concen-coagulation tests fail to truly reﬂect the balance of procoag- trations, are employed to initiate or amplify clot formation.ulant and anticoagulant factors in vivo [2]. Although these ideas Secondly, tests such as the PT and APTT measure onlyare essentially valid, the relationship between abnormal procoagulant factors and it is known that the balance betweenhemostasis tests and the risk of bleeding in cirrhotics cannot the procoagulant and anticoagulant pathways is critical [2].be discarded. Thirdly, PT and APTT do not allow full activation of protein C, whose levels are reduced in advanced cirrhosis [2]. Fourthly, these tests have a relatively poor sensitivity for the detection ofChronic liver disease: effect on hemostasis tests low clotting factors [3] and clot formation occurs after onlyLiver cirrhosis is characterized by a defective hepatic little of the whole thrombin is generated [7]. However, thesesynthesis of clotting factors and thrombocytopenia, mainly limitations do not apply only to liver cirrhosis, but also tocaused by portal hypertension, and by hyperﬁbrinolysis that nearly all acquired coagulopathies associated with multiplemay further contribute to alterations in hemostasis [3]. Other factor deﬁciencies. They apply, for instance, to oral anticoagu-abnormalities, such as disseminated intravascular coagulation lant therapy with anti-vitamin K drugs that, like liver disease,(DIC), dysﬁbrinogenemia, vitamin K deﬁciency, or impaired affects multiple clotting factors and the protein C pathwayplatelet function, may be the additional contributing factors simultaneously. Yet the value of the PT in predicting the risk of[3]. bleeding is well established in patients on oral anticoagulant It has long been considered, somewhat simplistically, that therapy. The International Normalized Ratio (INR), whichcoagulation defects in liver disease may be measured through takes into account the sensitivity of the thromboplastinthe prolongation of such global screening tests as the employed, was a substantial advance for the standardizationprothrombin time (PT) and the activated partial thromboplas- of oral anticoagulant therapy, because it permits comparison oftin time (APTT). In the early phases of cirrhosis, the PT is results obtained in different laboratories and the establishmentusually within the normal range or only moderately prolonged, of universally valid therapeutic ranges. In the other acquiredmainly because of low factor VII (FVII) levels [4]. In more coagulopathies, including liver cirrhosis, PT standardizationadvanced cirrhosis, the prolonged PT is related to the severity using the INR is inadequate [8–10], because the slope of theof liver failure and is one of the parameters used in such linear regression obtained in the comparison of thromboplas- tins [which deﬁnes the International Sensitivity Index (ISI) usedCorrespondence: J. C. Reverter, Haemotherapy and Haemostasis for INR calculation] is clearly different in warfarin-treated andDepartment, Hospital Clı́nic, University of Barcelona, Barcelona, in liver cirrhosis patients [8]. Therefore, in liver cirrhosis the useSpain. of the INR may increase, instead of reducing, between-e-mail: reverter@clinic.ub.es laboratory variability.

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718 J. C. Reverter

In addition to such global screening tests such as the PT and mechanisms modulating the severity of gastrointestinal bleed-APTT, single clotting factors may be measured in patients with ing in these patients (involving hemodynamic changes,chronic liver disease, although there is currently little evidence thrombocytopenia and impaired platelet function, hyperﬁbrin-of their clinical utility. Although the determination of FV and olysis and low coagulation factors) makes the assessment of theFVII activity seems to be useful in acute hepatic failure, the separate role of each factor difﬁcult. In a recent double-blindmeasurement of single clotting factors adds little information to controlled trial, the use of recombinant activated FVII, a drugscreening tests in chronic liver disease [3]. More sensitive assays that improves clot formation [24], enhanced the initial controlsuch as the prothrombin fragment 1+2, ﬁbrinopeptide A, of variceal bleeding achieved with state-of-the-art medicalsoluble ﬁbrin, D-dimer, thrombin–antithrombin complexes therapy and allowed a much higher rate of survival free fromand plasmin-a-2-antiplasmin complexes have been used to early rebleeding in patients with advanced liver disease [25].diagnose intravascular coagulation in liver cirrhosis [11], but Moreover, in liver transplantation, prophylactic administrationtheir clinical relevance remains unclear. The same may be said of antiﬁbrinolytic agents such as aprotinin and tranexamic acidfor hyperﬁbrinolysis, which can be diagnosed using such tests reduces transfusion requirements [26,27]. The clinical relevanceas the euglobulin clot lysis time and plasma D-dimer. The of hyperﬁbrinolysis in the bleeding tendency seen in chronicmajority of studies of primary hemostasis are on the platelet liver disease patients is unclear. Bleeding from esophagealcount. A relationship between moderate to severely reduced varices in cirrhosis patients overlaps the circadian rhythm ofplatelet count and the presence of gastroesophageal bleeding ﬁbrinolysis [28] and hyperﬁbrinolysis was found to be the mainhas been demonstrated [12,13], whereas there is little informa- predictive marker of the ﬁrst episode of upper gastrointestinaltion on the predictive value of platelet function tests. bleeding in cirrhotic patients with portal hypertension [29]. However, no relationship between variceal bleeding and hyperﬁbrinolysis was found in other studies [22]. AlthoughBleeding in chronic liver disease: the role of hemostasis accelerated ﬁbrinolysis may increase bleeding from mucosalBleeding is a frequent and often severe complication of liver membranes and particularly gastrointestinal bleeding [29,30],cirrhosis. The most frequent and potentially life-threatening its true role as a trigger of gastroesophageal bleeding remainssite is the gastrointestinal tract. However, cirrhotics may also speculative.present with other signs of a bleeding tendency, including Taking all these data into account, it seems that the bleedingbruising, petechiae, purpura, ecchymosis, epistaxis, gingival manifestations of patients with liver disease depend, at least inbleeding and menorrhagia [3]. Hematomas occurring sponta- part, on the degree of hemostatic impairment. It is unlikely thatneously or after minimal trauma are common in advanced liver coagulopathy plays a crucial role in initiating variceal bleeding,disease and may be severe in some cases [14]. In addition, but it may be clinically relevant in aggravating it and facilitatingpatients with advanced liver disease have an increased risk of recurrences [31].bleeding during invasive diagnostic and therapeutic proce-dures. For instance, cirrhotics undergoing abdominal surgery Hemostasis tests in the evaluation of the risk of bleedinghave a high risk of morbidity and mortality [15], with bleeding in chronic liver diseaseaccounting for 60% of all deaths from this procedure [16].Moreover, intraperitoneal bleeding is the main complication of In patients with congenital defects of hemostasis, cutaneous,liver biopsy in cirrhotics: in 0.4–0.5% of these procedures subcutaneous, mucosal and muscular bleeding is related tosigniﬁcant bleeding occurs [17] and in 0.01–0.1% it causes coagulation defects and to platelet alterations. In liver cirrhosis,death [18]. Hemostasis abnormalities are one of the main a similar involvement of these alterations has been hypothes-problems in patients undergoing liver transplantation and the ized but although a partial association between these types ofmortality of the procedure is positively associated with intra- bleeding and the degree of abnormalities of global coagulationand postoperative bleeding [19]. tests was found [22], sufﬁcient data to conﬁrm this hypothesis Hemodynamic alterations secondary to portal hypertension are not available.are considered the main cause of gastrointestinal bleeding in Gastrointestinal bleeding is mainly hemodynamic in itscirrhotics [2,20,21]. In addition, portal hypertension also mechanisms and is related to portal hypertension [21]. There-contributes signiﬁcantly to excessive intra- and postoperative fore, coagulation tests may have only a limited predictive valueblood loss during liver surgery [3]. The role played by the for bleeding tendency. In several studies, a prolonged PT hascoagulopathy of cirrhosis in gastrointestinal bleeding is still been associated with an increased risk of gastrointestinalunclear. It does not seem to play a major role in initiating bleeding in chronic liver disease [32–34]. However, the PT maybleeding; however, a relationship between the severity of reﬂect the risk in a way unrelated to the degree of coagulop-bleeding and the degree of coagulation defect was reported [22]. athy, because the decreased hepatic synthesis of coagulationClinical evidence indicates that variceal bleeding is more severe, factors, reﬂected globally by the PT, is an excellent marker ofmore difﬁcult to control and more likely to recur in patients liver failure and a strong independent prognostic indicator ofwith advanced liver failure (presenting with more prolonged survival in patients with chronic liver disease [23]. Patients withPT and, often, lower platelet counts) than in patients with moderately or severely prolonged PT have 5- to 10-foldrelatively preserved liver function [1,23]. The complexity of the higher mortality rates than patients with normal PT [35]. For

Ó 2006 International Society on Thrombosis and Haemostasis

Abnormal hemostasis tests and bleeding in chronic liver disease 719

this reason, new and old prognostic indexes for patients with chronic liver disease, the PT will continue to be used to estimateadvanced liver disease include the PT as one component the bleeding tendency. In part because of its relationship with[23,36]. The presence or absence of severe gastrointestinal coagulopathy but mainly as a good, simple, inexpensive,bleeding is a major determinant of survival in these patients, quantitative and accurate prognostic marker of liver impair-and the prognostic indexes, which include the PT, reﬂect this ment, which, in turn, is a predictor of bleeding [3].fact. The degree of PT impairment as an expression ofdecreased liver synthesis also predicts the severity of portal Referenceshypertension and the presence of esophageal varices [12].Therefore, measuring the PT provides an indirect evaluation of 1 Hedner U, Erhardtsen E. Hemostatic disorders in liver diseases.both the main components of the bleeding tendency in In: Schiﬀ ER, Sorrell MF, Maddrey WC, eds. Schiﬀ’s Diseases of the Liver. Philadelphia: Lippincott Williams & Wilkins, 2003: 625–cirrhosis: portal hypertension and coagulopathy. 36. The role of hemostasis tests in predicting bleeding accom- 2 Tripodi A, Salerno F, Chantarangkul V, Clerici M, Cazzaniga M,panying liver biopsy or surgical procedures in patients with Primignani M, Mannucci PM. Evidence of normal thrombin genera-cirrhosis is controversial. Although the PT and the platelet tion in cirrhosis despite abnormal conventional coagulation tests.count are used to evaluate the bleeding risk in patients Hepatology 2005; 41: 553–8. 3 Amitrano L, Guardascione MA, Brancaccio V, Balzano A. Coagula-undergoing liver biopsy, several studies found no increased tion disorders in liver disease. Semin Liver Dis 2002; 22: 83–96.risk of bleeding associated with moderate prolongations of 4 Green G, Poller L, Thomsen JM, Dymock IW. Factor VII as a markerthe PT [17,18]. However, when the prolongation of the PT is of hepatocellular synthetic function in liver disease. J Clin Pathol 1976;severe, the risk of bleeding increases dramatically [37]. No 29: 971–5.coagulation parameter was related to the bleeding time as 5 Pugh RN, Murray-Lyon IM, Dawson JL, Pietroni MC, Williams R. Transection of the oesophagus for bleeding oesophageal varices. Br Jmeasured from the liver at laparoscopy [38] and a moderate Surg 1973; 60: 646–9.to mild thrombocytopenia does not increase clinically 6 Forman LM, Lucey MR. Predicting the prognosis of chronic liverrelevant bleeding in liver biopsy [18,37]. Routine use of the disease: an evolution from child to MELD. Mayo end-stage liverbleeding time as an indicator of the risk of bleeding during disease. Hepatology 2001; 33: 473–5.liver biopsy remains controversial [39]. The preoperative PT 7 Mann KG, Brummel K, Butenas S. What is all that thrombin for? J Thromb Haemost 2003; 1: 1504–14.has been associated both with the risk of bleeding and 8 Robert A, Chazouillères O. Prothrombin time in liver failure: time,mortality, (mainly because of bleeding), in surgical proce- ratio, activity percentage, or international normalized ratio? Hepatol-dures in cirrhotics [16,35]. The PT and the platelet count have ogy 1996; 24: 1392–4.also been reported to be predictive of bleeding during 9 Trotter JF, Brimhall B, Arjal R, Phillips C. Speciﬁc laboratorylaparoscopic procedures in cirrhotics [40]. However, other methodologies achieve higher model for endstage liver disease (MELD) scores for patients listed for liver transplantation. Liverreports indicate that the PT and APTT might be inadequate Transpl 2004; 10: 995–1000.to assess the true risk of bleeding when patients with cirrhosis 10 WHO Expert Committee on Biological Standardization. Guidelinessundergo invasive procedures [2]. In liver transplantation this for Thromboplastins and Plasma used to Control Oral Anticoagulantrelationship is not so clear [41], but the impact of massive Therapy. Technical Report Series 889; 48th report, Geneva, Switzer-transfusions and the relevance of local surgical wounds must land, 1999. 11 Joist JH. AICF and DIC in liver cirrhosis: Expressions of a hyper-be considered. coagulable state. Am J Gastroenterol 1999; 94: 2801–3. 12 Schepis F, Cammà C, Niceforo D, Magnano A, Pallio S, Cinquegrani M, D’amico G, Pasta L, Craxi A, Saitta A, Raimondo G. WhichFuture developments and conclusions patients with cirrhosis should undergo endoscopic screening for eso-New tests that evaluate more accurately than now hemostasis phageal varices detection?. Hepatology 2001; 33: 333–8. 13 Zaman A, Hapke R, Flora K, Rosen HR, Benner K. Factorsalterations in cirrhotics are needed to redeﬁne the role of these predicting the presence of esophageal or gastric varices in patients withalterations in the clinical bleeding tendency of these patients. advanced liver disease. Am J Gastroenterol 1999; 94: 3292–6.The most promising is the endogenous thrombin potential [2], 14 Erlinger S, Benhamou P. Cirrhosis: clinical aspects. In: McIntyre N,although technical complexity and cost make its introduction Benhamou JP, Bircher J, Rizzetto M, Rodes J, eds. Oxford Text-into routine clinical evaluation difﬁcult at the moment. For book of Clinical Hepatology. Oxford: Oxford University Press, 1991: 380–90.studies of platelet function, the limitations of classical aggrego- 15 Friedman LS. The risk of surgery in patients with liver disease. Hep-metry may probably be circumvented by new automated global atology 1999; 29: 1617–23.screening devices of platelet function such as the Platelet 16 Aranha GV. Cholecystectomy in cirrhotic patients: a formidableFunction Analyzer-100 (PFA-100) [42] or and the Clot operation. Am J Surg 1982; 143: 55–60.Signature Analyzer [43]. However, there is currently little 17 McGill DB, Rakela J, Zinsmeister AR, Ott BJ. A 21-year experience with major haemorrhage after percutaneous liver biopsy. Gastro-information available on its use in liver disease. enterology 1990; 99: 1396–400. In conclusion, although hemostasis does not contribute to 18 Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications follow-bleeding in chronic liver disease as much as it was once thought, ing percutaneous liver biopsy. J Hepatol 1986; 2: 165–73.this does not mean that the PT should no longer be used to 19 Ozier Y, Steib A, Ickx B, Nathan N, Derlon A, Guay J, De Moerlooseevaluate the bleeding risk in patients with liver cirrhosis. While P. Haemostatic disorders during liver transplantation. Eur J Anaes- thesiol 2001; 18: 208–18.waiting for more ÔphysiologicalÕ tests to evaluate hemostasis in